Image credit: American Academy of Ophthalmology. Used with permission for educational purposes.

Horner syndrome describes the constellation of findings associated with a lesion affecting the oculosympathetic pathway. Clinically, ipsilateral miosis, ptosis, and anhidrosis form the classic triad, with other features potentially being present.

Without getting into too much detail about the sympathetic pathways and differential diagnosis of Horner syndrome (those will be covered in other articles), I will attempt to highlight the 3 pharmaceutical agents used in the diagnosis of Horner syndrome, discuss the tests, and point out the key ideas that often find themselves in tests.

Caveat: Because of the general unavailability of some of these drugs (namely cocaine and hydroxyamphetamine) and the relatively lower cost/availability of neuroimaging, these drugs may not be available to your local neuro-ophthalmologist. There are evolving discussions about navigating the challenges of diagnosis given these limitations (1, 2). Despite these changes to practical clinical evaluation, it remains clinically important to understand the pharmacologic principles involved in the diagnosis of Horner syndrome.

Classification

The pharmacologic diagnosis of Horner syndrome can be broken into two major categories:

Diagnostic Drops

Cocaine

The cocaine test for Horner syndrome is often tested in board exam/OKAP settings, most likely because of its understood mechanism of action, its contribution to the understanding/diagnosis of Horner syndrome, and somewhat counterintuitive testing results.

From a practical standpoint, relatively few clinics have cocaine available for Horner syndrome testing, largely due to the unavailability, high cost with no reimbursement, and security requirements for storage. So although cocaine is discussed from a historical context, we unfortunately have to also learn the details of this test so that you can easily answer any questions that might pop up on a test. Just don’t be surprised if you can’t find any doctors who can do a cocaine test for Horner (it might not be necessary anyways).

Mechanism of action: blocks the reuptake of norepinephrine into presynaptic neurons at the synapse of postganglionic sympathetic nerves and muscle (in eye drops, synapse of long ciliary nerves and iris dilator muscle).

Cocaine test for Horner syndrome (19).

A. Before drops administered (suspected right Horner syndrome).

B. After drops administered. Note that there is some pupil dilation in the right eye, but the amount of anisocoria is ≥1 mm.

Instill 1 drop of cocaine (4% or 10%) in each eye, wait 5 minutes, then an additional 1 drop of cocaine in each eye

Wait 40-60 minutes

Remeasure pupil size of both eyes

Results:

No reaction after 60 minutes: put one more drop of cocaine, wait another 30 minutes

Pupillary inequality ≥ 1.0 mm: positive test for Horner syndrome (the greater the inequality, the more accurate it gets)

Pupillary inequality < 1.0 mm: negative test for Horner syndrome

Considerations:

Urine drug test for cocaine will be positive for a few days after testing (5)

Apraclonidine

Apraclonidine is the most readily available drug used for confirming Horner syndrome. Because this drop is often available in comprehensive ophthalmology clinics for other uses (it lowers IOP and may be used as a pre- or post-treatment for in-office procedures), knowing how to administer this test may be helpful for confirming Horner syndrome, especially if neuro-ophthalmology is not readily available.

Denervation must be present long enough for receptor upregulation to have occurred (14)

Positive tests have been noted within hours of a carotid dissection but the onset of denervation sensitivity are variable (15)

False negatives can occur in the setting of acute Horner syndrome or in long-standing cases if strict “reversal of anisocoria” criteria used (16, 17)

Apraclonidine has limited use in pediatric Horner syndrome due to the risk of CNS and respiratory depression (18)

Hydroxyamphetamine

Hydroxyamphetamine remains a useful tool for localization of the lesion once a diagnosis of Horner syndrome has been confirmed (20). However, it is limited by accessibility and some considerations detailed below. Since it’s still tested (and important to understand from a mechanistic and historical perspective), you still need to know how it works and what it does.

Mechanism of action: increases the release of norepinephrine from the presynaptic neuron (21). In intact presynaptic (3rd order, postganglionic) neurons, this results in pupil dilation; if this neuron is not intact, the pupil does not dilate.

Hydroxyamphetamine test for Horner syndrome (19, 21).

A. Before drops administered (suspected right Horner syndrome).

B. After drops administered. Note the dilation of both pupils. This indicates an intact 3rd-order, postganglionic neuron and localizes the lesion to the 1st-order (central) or 2nd-order (preganglionic) neuron.

Image credit: Modified from clinical images courtesy of Lanning B. Kline, M.D. American Academy of Ophthalmology. Used with permission for educational purposes.

Test (21-25):

Note anisocoria (which pupil is small, which pupil is larger)

Instill 1 drop of hydroxyamphetamine (1%) in each eye

Wait 45-60 minutes

Re-evaluate anisocoria

Results:

In patients with normal pupils, there is a symmetric 2 mm dilation of each pupil (anisocoria remains) (22).

In patients with Horner syndrome, the reaction is based on whether or not there is an intact 3rd-order (postganglionic) neuron (23):

Cocaine interferes with the uptake and efficacy of hydroxyamphetaine; as such, if cocaine is used for confirming the diagnosis, at least 72 hours must pass before hydroxyamphetamine testing is done (26).

In cases where there is concern for rapid diagnosis and localization (such as in carotid dissection), don’t delay neuroimaging for the hydroxyamphetamine test!

In acute Horner syndrome, hydroxyamphetamine testing may produce a false-negative result during the first week after injury (27-28).

Video Lecture

Dr. Andrew Lee is a highly-regarded neuro-ophthalmologist and a phenomenal educator. He has made some short lecture videos on neuro-ophthalmology available on YouTube!